Post by Amanda McFarlan
What's the science?
Epidural electrical stimulation is a therapeutic treatment for individuals with spinal cord injuries that involves applying continuous electrical current to the lower part of the spinal cord. This technique has been shown to restore movement in animal models of spinal cord injury, but has been less effective in treating humans. It is hypothesized that action potentials induced by epidural electrical stimulation may collide with naturally-occurring action potentials conveying proprioceptive information (information about where one’s body is in space), disrupting the flow of information traveling to the brain. This may be a larger issue for humans compared to smaller mammals. This week in Nature Neuroscience, Formento and colleagues investigated why treatment of spinal cord injury with epidural electrical stimulation is less effective in humans compared to other mammals.
How did they do it?
The authors tested whether epidural electrical stimulation produces action potentials that travel in the opposite direction (i.e. towards the periphery, away from the brain) from that of sensory afferents (nerve fibers). To do this, they inserted subcutaneous needle electrodes in 2 patients with chronic spinal cord injury and recorded from their sural nerve, the proximal and distal branches of their tibial nerve, and their soleus muscle while applying epidural electrical stimulation. They also developed a computational model of proprioceptive afferents in rats and in humans to determine the probability of having a collision between naturally occurring action potentials and action potentials induced by epidural electrical stimulation. Next, they aimed to determine whether epidural electrical stimulation disrupts proprioception in humans. They had 2 participants with spinal cord injuries sit in a robotic system that passively moved their leg and asked the participants to indicate the direction of movement of their leg as they perceived it (measuring proprioception). They performed this experiment with and without epidural electrical stimulation. In subsequent experiments, they developed computational models to investigate the underlying mechanisms responsible for the disruption of proprioception in humans treated with epidural electrical stimulation. They used these models to investigate the impact of epidural electrical stimulation on proprioceptive feedback circuits during movement in rats and humans. Lastly, they examined how targeting a smaller pool of afferents with high-frequency, low amplitude bursts (rather than targeting all sensory afferents with continuous electrical stimulation) may resolve the issue of disrupted proprioception.
What did they find?
The authors found that epidural electrical stimulation elicited responses in the proximal and distal branches of the tibial nerve as well as the sural nerve. These responses occurred before motor responses in the soleus muscle, suggesting that these action potentials were traveling in the opposite direction of sensory afferents (i.e. towards the periphery). Using a computational model, the authors determined that the probability of having a collision between a naturally occurring action potential and an action potential induced by epidural electrical stimulation was much higher in humans compared to rats. They determined that patients were able to correctly identify the direction of movement 100% of the time in the absence of epidural electrical stimulation. In contrast, when electrical stimulation was delivered at 1.5 times stronger than the muscle response threshold, patients were not able to identify the direction of movement as they lacked awareness of their leg position and motion. These findings suggest that action potentials traveling in the opposite direction of naturally occurring action potentials in sensory afferents may be responsible for blocking proprioceptive information from reaching the brain in humans, but not rats. Furthermore, when assessing proprioceptive feedback circuits during movement, the authors showed that epidural electrical stimulation blocked proprioception in humans, but not rats, and that this interfered with the recruitment of alternating antagonist motor neurons required to produce movement. Finally, a computational model revealed that high-frequency bursts of epidural electrical stimulation targeting smaller population of sensory afferents greatly reduced the amount of proprioceptive information that was blocked with continuous electrical stimulation. These findings suggest that a high-frequency, low-amplitude stimulation protocol may be key for treating human patients with spinal cord injuries with epidural electrical stimulation. Note: In a companion study published in Nature at the same time, the authors implemented their spatially selective stimulation approach in spinal cord injury patients and found it to be beneficial.
What's the impact?
This is the first study to show that treatment with continuous epidural electrical stimulation is less efficient in humans compared to other small mammals because it disrupts proprioception. Further studies focused on improving electrical stimulation protocols will provide insight into how proprioception can be better preserved to make this technique useful for treating humans with spinal cord injuries. Improving this technique could be instrumental in helping individuals suffering from spinal cord injuries regain mobility.
Formento et al. Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury. Nature Neuroscience (2018). Access to the original scientific publication here.